Dihydropteridinone Compounds

ABSTRACT

Disclosed are new dihydropteridinones of general formula (I) 
     
       
         
         
             
             
         
       
     
     wherein the groups L and R 1 -R 5  have the meanings given in the claims and specification, the isomers thereof, intermediates and processes for preparing these dihydropteridinones and the use thereof as pharmaceutical compositions.

RELATED APPLICATION DATA

This application is a continuation application of U.S. application Ser.No. 11/219,728 filed May 30, 2008, which is a divisional of U.S. Pat.No. 7,786,299 filed Sep. 6, 2005, which is a continuation of U.S.application Ser. No. 10/903,807 filed Jul. 30, 2004, which is acontinuation of U.S. Pat. No. 6,681,422 filed Feb. 26, 2003.

The present invention relates to new dihydropteridinones of generalformula (I)

wherein the groups L, R¹, R², R³, R⁴ and R⁵ have the meanings given inthe claims and specification, the isomers thereof, processes forpreparing these dihydropteridinones and the use thereof aspharmaceutical compositions.

BACKGROUND TO THE INVENTION

Pteridinone derivatives are known from the prior art as activesubstances with an antiproliferative activity. WO 01/019825 describesthe use of pteridinone derivatives for the treatment of neoplastic andviral diseases. The resistance of many types of tumours calls for thedevelopment of new pharmaceutical compositions for combating tumours.

The aim of the present invention is to prepare new compounds withantiinflammatory and antiproliferative activity.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly it has been found that compounds of general formula (I)wherein the groups L and R¹ to R⁵ have the meanings given hereinafteract as inhibitors of specific cell cycle kinases. Thus, the compoundsaccording to the invention may be used for example to treat diseasesconnected with the activity of specific cell cycle kinases andcharacterised by excessive or abnormal cell proliferation.

The present invention therefore relates to compounds of general formula(I)

whereinR¹, R² which may be identical or different, denote hydrogen oroptionally substituted C₁-C₆-alkyl,orR¹ and R² together denote a 2- to 5-membered alkyl bridge which maycontain 1 to 2 heteroatoms,R³ denotes hydrogen or a group selected from among optionallysubstituted C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl andC₆-C₁₄-aryl, ora group selected from among optionally substituted and/or bridgedC₃-C₁₂-cycloalkyl, C₃-C₁₂-cycloalkenyl, C₇-C₁₂-polycycloalkyl,C₇-C₁₂-polycycloalkenyl, C₅-C₁₂-spirocycloalkyl, C₃-C₁₂-heterocycloalkylwhich contains 1 to 2 heteroatoms, and C₃-C₁₂-heterocycloalkenyl whichcontains 1 to 2 heteroatoms, orR¹ and R³ or R² and R³ together denote a saturated or unsaturatedC₃-C₄-alkyl bridge which may contain 1 heteroatom,R⁴ denotes a group selected from among hydrogen, —CN, hydroxy, —NR₆R₇and halogen, ora group selected from among optionally substituted C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₅-alkyloxy, C₂-C₅-alkenyloxy,C₂-C₅-alkynyloxy, C₁-C₆-alkylthio, C₁-C₆-alkylsulphoxo andC₁-C₆-alkylsulphonyl,L denotes a linker selected from among optionally substitutedC₂-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₆-C₁₄-aryl, —C₂-C₄-alkyl-C₆-C₁₄-aryl,—C₆-C₁₄-aryl-C₁-C₄-alkyl, optionally bridged C₃-C₁₂-cycloalkyl andheteroaryl which contains 1 or 2 nitrogen atoms,n denotes 0 or 1m denotes 1 or 2R⁵ denotes a group selected from among optionally substitutedmorpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl,pyrrolidinyl, tropenyl, R⁸-diketomethylpiperazinyl, sulphoxomorpholinyl,sulphonylmorpholinyl, thiomorpholinyl, —NR⁸R⁹ and azacycloheptyl,R⁶, R⁷ which may be identical or different, denote hydrogen orC₁-C₄-alkyl,andR⁸, R⁹ denote unsubstituted nitrogen substituents at R⁵, which may beidentical or different, denote either hydrogen or a group selected fromamong C₁-C₆-alkyl, —C₁-C₄-alkyl-C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl,C₆-C₁₄-aryl, —C₁-C₄-alkyl-C₆-C₁₄-aryl, pyranyl, pyridinyl, pyrimidinyl,C₁-C₄-alkyloxycarbonyl, C₆-C₁₄-arylcarbonyl, C₁-C₄-alkylcarbonyl,C₆-C₁₄-arylmethyloxycarbonyl, C₆-C₁₄-arylsulphonyl,C₁-C₄-alkylsulphonyl- and C₆-C₁₄-aryl-C₁-C₄-alkylsulphonyl-, optionallyin the form of the tautomers, the racemates, the enantiomers, thediastereomers and the mixtures thereof, and optionally thepharmacologically acceptable acid addition salts thereof.

Preferred compounds of formula (I) are those wherein

R¹ to R⁴, R⁶ and R⁷ are as hereinbefore defined, andL denotes a linker selected from among optionally substitutedC₂-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₆-C₁₄-aryl, —C₂-C₄-alkyl-C₆-C₁₄-aryl,—C₆-C₁₄-aryl-C₁-C₄-alkyl, optionally bridged C₃-C₁₂-cycloalkyl andheteroaryl which contains 1 or 2 nitrogen atomsn denotes 1m denotes 1 or 2R⁵ denotes a group which is bound to L via a nitrogen atom, selectedfrom among optionally substituted morpholinyl, piperidinyl,R⁸-piperazinyl, pyrrolidinyl, tropenyl, R⁸-diketomethylpiperazinyl,sulphoxomorpholinyl, sulphonylmorpholinyl, thiomorpholinyl, —NR⁸R⁹ andazacycloheptyl,R⁸, R⁹ denote unsubstituted nitrogen substituents at R⁵, which may beidentical or different, hydrogen or a group selected from amongC₁-C₆-alkyl, —C₁-C₄-alkyl-C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl,C₆-C₁₄-aryl, —C₁-C₄-alkyl-C₆-C₁₄-aryl, pyranyl, pyridinyl, pyrimidinyl,C₁-C₄-alkyloxycarbonyl, C₆-C₁₄-arylcarbonyl, C₁-C₄-alkylcarbonyl,C₆-C₁₄-arylmethyloxycarbonyl, C₆-C₁₄-arylsulphonyl, C₁-C₄-alkylsulphonyland C₆-C₁₄-aryl-C₁-C₄-alkylsulphonyl,optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, and optionally thepharmacologically acceptable acid addition salts thereof.

Also preferred are compounds of formula (I), wherein

R¹ to R⁴, R⁶ and R⁷ are as hereinbefore defined,L denotes a linker selected from among optionally substitutedC₂-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₆-C₁₄-aryl, —C₂-C₄-alkyl-C₆-C₁₄-aryl,—C₆-C₁₄-aryl-C₁-C₄-alkyl, optionally bridged C₃-C₁₂-cycloalkyl andheteroaryl which contains 1 or 2 nitrogen atomsn denotes 0 or 1m denotes 1 or 2R⁵ denotes a group which is bound to L via a carbon atom, selected fromamong R⁸-piperidinyl, R⁸R⁹-piperazinyl, R⁸-pyrrolidinyl,R⁸-piperazinylcarbonyl, R⁸-tropenyl, R⁸-morpholinyl andR⁸-azacycloheptyl,andR⁸, R⁹ denote unsubstituted nitrogen substituents at R⁵, which may beidentical or different, hydrogen or a group selected from amongC₁-C₆-alkyl, —C₁-C₄-alkyl-C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl,C₆-C₁₄-aryl, —C₁-C₄-alkyl-C₆-C₁₄-aryl, pyranyl, pyridinyl, pyrimidinyl,C₁-C₄-alkyloxycarbonyl, C₆-C₁₄-arylcarbonyl, C₁-C₄-alkylcarbonyl,C₆-C₁₄-arylmethyloxycarbonyl, C₆-C₁₄-arylsulphonyl, C₁-C₄-alkylsulphonyland C₆-C₁₄-aryl-C₁-C₄-alkylsulphonyl,optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, and optionally thepharmacologically acceptable acid addition salts thereof.

Particularly preferred are compounds of formula I wherein

L, m, n and R³ to R⁹ are as hereinbefore defined, andR¹, R² which may be identical or different, denote a group selected fromamong hydrogen, Me, Et, Pr, orR¹ and R² together form a C₂-C₄-alkyl bridge,optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, and optionally thepharmacologically acceptable acid addition salts thereof.

Especially preferred are compounds of formula I wherein

R¹, R², m, n and R⁵ to R⁸ are as hereinbefore defined, andR³ denotes a group selected from among optionally substitutedC₁-C₁₀-alkyl, C₃-C₇-cycloalkyl, C₃-C₆-heterocycloalkyl and C₆-C₁₄-arylorR¹ and R³ or R² and R³ together denote a saturated or unsaturatedC₃-C₄-alkyl bridge which may contain 1 to 2 heteroatoms,R⁴ denotes a group selected from among hydrogen, OMe, OH, Me, Et, Pr,OEt, NHMe, NH₂, F, CL, Br, O-propargyl, O-butynyl, CN, SMe, NMe₂, CONH₂,ethynyl, propynyl, butynyl and allyl,andL denotes a linker selected from among optionally substituted phenyl,phenylmethyl, cyclohexyl and branched C₁-C₆-alkyl,optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, and optionally thepharmacologically acceptable acid addition salts thereof.

The invention further relates to compounds of formula I for use aspharmaceutical compositions.

Of particular importance according to the invention are compounds offormula I for use as pharmaceutical compositions with anantiproliferative activity.

The invention also relates to the use of a compound of formula I forpreparing a pharmaceutical composition for the treatment and/orprevention of cancer, infections, inflammatory and autoimmune diseases.

The invention also relates to a method of treating and/or preventingcancer, infections, inflammatory and autoimmune diseases, characterisedin that a patient is given an effective amount of a compound of formulaI.

The invention also relates to pharmaceutical preparations, containing asactive substance one or more compounds of general formula (I) or thephysiologically acceptable salts thereof, optionally combined withconventional excipients and/or carriers.

The invention also relates to a process for preparing a compound ofgeneral formula (I),

whereinR¹-R⁵, m, n and L are as hereinbefore defined,characterised in that a compound of general formula (II)

whereinR¹-R³ are as hereinbefore defined and A is a leaving group, is reactedwith an optionally substituted compound of general formula (III),

whereinR⁴ is as hereinbefore defined andR¹⁰ denotes OH, NH-L-R⁵, —O-methyl, —O-ethyl,and optionally then the product of general formula (IV)

whereinR¹ to R⁴ is as hereinbefore defined andR¹⁰ denotes OH, —NH-L-R⁵, —O-methyl or —O-ethyl,optionally after previous hydrolysis of the ester group —COR¹⁰, isreacted with an amine of general formula (V)

NH₂-L-R⁵ _(m)  (V)

whereinR⁵ is as hereinbefore defined.

The invention further relates to a compound of formula (II),

whereinR¹-R³ are as hereinbefore defined and A is a leaving group.

The term alkyl groups, including alkyl groups which are a part of othergroups, denotes branched and unbranched alkyl groups with 1 to 12 carbonatoms, preferably 1-6, most preferably 1-4 carbon atoms, such as, forexample: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,nonyl, decyl and dodecyl. Unless otherwise stated, the abovementionedterms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl anddodecyl include all the possible isomeric forms. For example, the termpropyl includes the two isomeric groups n-propyl and iso-propyl, theterm butyl includes n-butyl, iso-butyl, sec. butyl and tert.-butyl, theterm pentyl includes iso-pentyl, neopentyl, etc.

In the abovementioned alkyl groups one or more hydrogen atoms mayoptionally be replaced by other groups. For example these alkyl groupsmay be substituted by fluorine. All the hydrogen atoms of the alkylgroup may optionally also be replaced.

The term alkyl bridge, unless otherwise stated, denotes branched andunbranched alkyl groups with 1 to 5 carbon atoms, for example methylene,ethylene, propylene, isopropylene, n-butylene, iso-butyl, sec. butyl andtert.-butyl etc. bridges. Methylene, ethylene, propylene and butylenebridges are particularly preferred. In the alkyl bridges mentioned 1 to2 C-atoms may optionally be replaced by one or more heteroatoms selectedfrom among oxygen, nitrogen or sulphur.

The term alkenyl groups (including those which are a part of othergroups) denotes branched and unbranched alkylene groups with 2 to 10carbon atoms, preferably 2-6 carbon atoms, most preferably 2-3 carbonatoms, provided that they have at least one double bond. Examplesinclude: ethenyl, propenyl, butenyl, pentenyl etc. Unless otherwisestated, the abovementioned terms propenyl, butenyl, etc also include allthe possible isomeric forms. For example, the term butenyl includes1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl and1-ethyl-1-ethenyl.

In the abovementioned alkenyl groups, unless otherwise stated, one ormore hydrogen atoms may optionally be replaced by other groups. Forexample, these alkyl groups may be substituted by the halogen atomfluorine. All the hydrogen atoms of the alkenyl group may optionallyalso be replaced.

The term alkynyl groups (including those which are a part of othergroups) denotes branched and unbranched alkynyl groups with 2 to 10carbon atoms, provided that they have at least one triple bond, forexample ethynyl, propargyl, butynyl, pentynyl, hexynyl etc., preferablyethynyl or propynyl.

In the abovementioned alkynyl groups, unless otherwise stated, one ormore hydrogen atoms may optionally be replaced by other groups. Forexample, these alkyl groups may be substituted by fluorine. All thehydrogen atoms of the alkynyl group may optionally also be replaced.

The term aryl denotes an aromatic ring system with 6 to 14 carbon atoms,preferably 6 or 10 carbon atoms, preferably phenyl, which, unlessotherwise stated, may carry one or more of the following substituents,for example: OH, NO₂, CN, OMe, —OCHF₂, —OCF₃, —NH₂, halogen, for examplefluorine or chlorine, C₁-C₁₀-alkyl, preferably C₁-C₅-alkyl, preferablyC₁-C₃-alkyl, most preferably methyl or ethyl, —O—C₁-C₃-alkyl, preferably—O-methyl or —O-ethyl, —COOH, —COO—C₁-C₄-alkyl, preferably —O-methyl or—O-ethyl, —CONH₂.

Examples of heteroaryl groups wherein up to two carbon atoms arereplaced by one or two nitrogen atoms include pyrrole, pyrazole,imidazole, triazole, pyridine, pyrimidine, while each of theabovementioned heteroaryl rings may optionally also be anellated to abenzene ring, preferably benzimidazole, and unless otherwise statedthese heterocycles may carry one or more of the following substituents,for example: F, Cl, Br, OH, OMe, methyl, ethyl, CN, CONH₂, NH₂,optionally substituted phenyl, optionally substituted heteroaryl,preferably optionally substituted pyridyl.

Examples of cycloalkyl groups are cycloalkyl groups with 3-12 carbonatoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl orcyclohexyl, while each of the abovementioned cycloalkyl groups mayoptionally also carry one or more substituents, for example: OH, NO₂,CN, OMe, —OCHF₂, —OCF₃, —NH₂ or halogen, preferably fluorine orchlorine, C₁-C₁₀-alkyl, preferably C₁-C₅-alkyl, preferably C₁-C₃-alkyl,more preferably methyl or ethyl, —O—C₁-C₃-alkyl, preferably —O-methyl or—O-ethyl, —COON, —COO—C₁-C₄-alkyl, preferably —COO-methyl or —COO-ethylor —CONH₂. Particularly preferred substituents of the cycloalkyl groupsare ═O, OH, NH₂, methyl or F.

Examples of cycloalkenyl groups are cycloalkyl groups with 3-12 carbonatoms which have at least one double bond, for example cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, preferablycyclopropenyl, cyclopententyl or cyclohexenyl, while each of theabovementioned cycloalkenyl groups may optionally also carry one or moresubstituents.

“═O” denotes an oxygen atom linked via a double bond.

Examples of heterocycloalkyl groups, unless otherwise described in thedefinitions, include 3- to 12-membered, preferably 5-, 6- or 7-membered,saturated or unsaturated heterocycles which may contain as heteroatomsnitrogen, oxygen or sulphur, for example tetrahydrofuran,tetrahydrofuranone, γ-butyrolactone, α-pyran, γ-pyran, dioxolane,tetrahydropyran, dioxane, dihydrothiophene, thiolan, dithiolan,pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline,imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine,piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan,oxazine, tetrahydro-oxazinyl, isothiazole, pyrazolidine, preferablymorpholine, pyrrolidine, piperidine or piperazine, while theheterocyclic group may optionally carry substituents, for exampleC₁-C₄-alkyl, preferably methyl, ethyl or propyl.

Examples of polycycloalkyl groups are optionally substituted, bi-, tri-,tetra- or pentacyclic cycloalkyl groups, for example pinane,2,2,2-octane, 2,2,1-heptane or adamantane. Examples of polycycloalkenylgroups are optionally bridged and/or substituted 8-membered bi-, tri-,tetra- or pentacyclic cycloalkenyl groups, preferably bicycloalkenyl ortricycloalkenyl groups, if they have at least one double bond, forexample norbornene.

Examples of spiroalkyl groups are optionally substituted spirocyclicC₅-C₁₂ alkyl groups.

Generally, the term halogen denotes fluorine, chlorine, bromine oriodine, preferably fluorine, chlorine or bromine, most preferablychlorine.

The leaving group A denotes either identical or different leaving groupssuch as for example -o-methyl, —SCN, chlorine, bromine, iodine,methanesulphonyl, trifluoromethanesulphonyl or p-toluenesulphonyl,preferably chlorine.

The compounds according to the invention may be present in the form ofthe individual optical isomers, mixtures of the individual enantiomers,diastereomers or racemates, in the form of the tautomers and also in theform of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids—such as for example acid additionsalts with hydrohalic acids, for example hydrochloric or hydrobromicacid, or organic acids, such as for example oxalic, fumaric, diglycolicor methanesulphonic acid.

The substituent R¹ may denote hydrogen or a group selected from amongoptionally substituted and/or branched C₁-C₆-alkyl, preferably methyl orethyl, more preferably methyl or ethyl.

The substituent R² may denote hydrogen or a group selected from amongoptionally substituted and/or branched C₁-C₆-alkyl, preferably methyl orethyl.

R¹ and R² together may denote a 2- to 5-membered alkyl bridge,preferably an ethylene, propylene or butylene bridge which may contain 1to 2 heteroatoms, preferably oxygen or nitrogen, more preferablyethylene, propylene.

The substituent R³ may denote hydrogen or a group selected from amongoptionally substituted and/or branched C₁-C₁₂-alkyl, preferably ethyl,propyl, butyl, pentyl or hexyl, more preferably propyl, butyl, pentyl orhexyl, C₂-C₁₂-alkenyl, preferably C₅-C₇-alkenyl, C₂-C₁₂-alkynyl,preferably C₅-C₇-alkynyl and C₆-C₁₄-aryl, preferably phenyl, a groupselected from among optionally substituted and/or bridgedC₃-C₁₂-cycloalkyl, preferably cyclopentyl or cyclohexyl,C₃-C₁₂-cycloalkenyl, preferably C₆-C₇-cycloalkenyl,C₇-C₁₂-polycycloalkyl, C₇-C₁₂-polycycloalkenyl, C₆-C₁₂-spirocycloalkyl,C₃-C₁₂-heterocycloalkyl, preferably pyranyl or piperinyl, pyrrolidinyl,pyrazinyl or morpholinyl which contains 1 to 2 heteroatoms, preferablyoxygen or nitrogen, and C₃-C₁₂-heterocycloalkenyl which contains 1 to 2heteroatoms, preferably oxygen or nitrogen.

Most preferably, the substituent R³ denotes isopropyl, isobutyl,isopentyl, cyclopentyl, phenyl or cyclohexyl.

R¹ and R³ or R² and R³ together may denote a saturated or unsaturatedC₃-C₄-alkyl bridge which may contain 1 heteroatom, preferably oxygen ornitrogen.

The substituent R⁴ may denote a group selected from among hydrogen, —CN,hydroxy, —NR⁶R⁷ and Halogen, preferably chlorine or fluorine, morepreferably chlorine or a group selected from among optionallysubstituted C₁-C₆-alkyl, preferably methyl, ethyl or propyl,C₂-C₆-alkenyl, preferably ethenyl or propenyl, C₂-C₆-alkynyl, preferablyethynyl, propynyl or butynyl, C₁-C₅-alkyloxy, preferably methoxy, ethoxyor propargyloxy, C₂-C₅-alkenyloxy, C₂-C₅-alkynyloxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulphoxo and C₁-C₆-alkylsulphonyl.

Most preferably, the substituent R⁴ denotes methoxy, methyl, ethoxy,ethyl, propargyloxy or chlorine.

L may denote a linker selected from among optionally substitutedC₂-C₁₀-alkyl, preferably ethyl, propyl, butyl or pentyl, C₂-C₁₀-alkenyl,C₆-C₁₄-aryl, preferably phenyl, —C₂-C₄-alkyl-C₆-C₁₄-aryl,—C₆-C₁₄-aryl-C₁-C₄-alkyl, preferably—phenyl-methyl, optionally bridgedC₃-C₁₂-cycloalkyl, preferably cyclohexyl, and heteroaryl which contains1 or 2 nitrogen atoms.

n denotes 0 or 1m denotes 1 or 2, preferably 1.R⁵ may denote a group selected from among optionally substitutedmorpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl,pyrrolidinyl, tropenyl, R⁸-diketomethylpiperazinyl, sulphoxomorpholinyl,sulphonylmorpholinyl, thiomorpholinyl, —NR⁸R⁹ and azacycloheptyl,preferably piperidinyl, morpholinyl, pyrrolidinyl, sulphoxomorpholiny,piperazinyl, thiomorpholinyl or tropenyl.

The groups R⁶ and R⁷ may be identical or different and may denotehydrogen or C₁-C₄-alkyl, preferably methyl or ethyl.

The groups R⁸ and R⁹ may be unsubstituted nitrogen substituents at R⁵,they may be identical or different and denote either hydrogen or a groupselected from among C₁-C₆-alkyl, preferably methyl, ethyl or propyl,—C₁-C₄-alkyl-C₃-C₁₀-cycloalkyl, preferably —CH₂-cyclopropyl,C₃-C₁₀-cycloalkyl, C₆-C₁₄-aryl, preferably phenyl,—C₁-C₄-alkyl-C₆-C₁₄-aryl, preferably benzyl, pyranyl, pyridinyl,pyrimidinyl, pyranyl, C₁-C₄-alkyloxycarbonyl, C₆-C₁₄-arylcarbonyl,C₁-C₄-alkylcarbonyl, C₆-C₁₄-arylmethyloxycarbonyl, C₆-C₁₄-arylsulphonyl,C₁-C₄-alkylsulphonyl and C₆-C₁₄-aryl-C₁-C₄-alkylsulphonyl.

Most preferably, the substituent R⁸ denotes methyl, ethyl or propyl.

Most preferably, the substituent R⁹ denotes methyl, ethyl or propyl.

R¹⁰ may be a substituent selected from among OH, NH₂-LR5, —O-methyl and—O-ethyl, preferably OH, LR5, —O-methyl or —O-ethyl.

All the groups mentioned in the definition of R¹ to R¹⁰ may optionallybe branched and/or substituted.

The compounds according to the invention may be prepared by synthesismethods A described hereinafter, while the substituents of generalformulae (A1) to (A9) have the meanings given hereinbefore. This methodis to be understood as an illustration of the invention withoutrestricting it to the subject matter thereof.

Method A Step 1A

A compound of formula (A1) is reacted with a compound of formula (A2) toobtain a compound of formula (A3) (Diagram 1A). This reaction may becarried out according to WO 0043369 or WO 0043372. Compound (A1) iscommercially obtainable, for example, from City Chemical LLC, 139Allings Crossing Road, West Haven, Conn., 06516, USA. Compound (A2) maybe prepared by procedures known from the literature: (a) F. Effenberger,U. Burkhart, J. Willfahrt Liebigs Ann. Chem. 1986, 314-333; b) T.Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995, 36, 6373-6374;c) R. K. Olsen, J. Org. Chem. 1970, 35, 1912-1915; d) F. E. Dutton, B.H. Byung Tetrahedron Lett. 1998, 30, 5313-5316; e) J. M. Ranajuhi, M. M.Joullie Synth. Commun. 1996, 26, 1379-1384.).

In Step 1A, 1 equivalent of the compound (A1) and 1 to 1.5 equivalents,preferably 1.1 equivalents of a base, preferably potassium carbonate,potassium hydrogen carbonate, sodium carbonate or sodium hydrogencarbonate, calcium carbonate, most preferably potassium carbonate, arestirred in a diluent optionally mixed with water, for example acetone,tetrahydrofuran, diethylether, cyclohexane, petroleum ether or dioxane,preferably cyclohexane or diethylether. At a temperature of 0 to 15° C.,preferably 5 to 10° C., 1 equivalent of an amino acid of formula (A2),dissolved in an organic solvent, for example acetone, tetrahydrofuran,diethylether, cyclohexane or dioxane, is added dropwise. The reactionmixture is heated to a temperature of 18° C. to 30° C., preferably about22° C., with stirring and then stirred for a further 10 to 24 hours,preferably about 12 hours. Then the diluent is distilled off, theresidue is combined with water and the mixture is extracted two to threetimes with an organic solvent, such as diethylether or ethyl acetate,preferably ethyl acetate. The combined organic extracts are dried andthe solvent is distilled off. The residue (compound A3) may be used inStep 2 without any prior purification.

Step 2A

The compound obtained in Step 1A (A3) is reduced at the nitro group andcyclised to form the compound of formula (A4) (Diagram 2A).

[Reduktion=reduction]

In Step 2A, 1 equivalent of the nitro compound (A3) is dissolved in anacid, preferably glacial acetic acid, formic acid or hydrochloric acid,preferably glacial acetic acid, and heated to 50 to 70° C., preferablyabout 60° C. Then a reducing agent, for example zinc, tin or iron,preferably iron filings, is added to complete the exothermic reactionand the mixture is stirred for 0.2 to 2 hours, preferably 0.5 hours, at100 to 125° C., preferably at about 117° C. After cooling to ambienttemperature the iron salt is filtered off and the solvent is distilledoff. The residue is taken up in a solvent or mixture of solvents, forexample ethyl acetate or dichloromethane/methanol 9/1 and semisaturatedNaCl solution, and filtered through kieselgur, for example. The organicphase is dried and evaporated down. The residue (compound (A4)) may bepurified by chromatography or by crystallisation or used as the crudeproduct in Step 3A of the synthesis.

Step 3A

The compound obtained in Step 2A (A4) may be reacted by electrophilicsubstitution as shown in Diagram 3A to obtain the compound of formula(A5).

In Step 3A 1 equivalent of the amide of formula (A4) is dissolved in anorganic solvent, for example dimethylformamide or dimethylacetamide,preferably dimethylacetamide, and cooled to about −5 to 5° C.,preferably 0° C.

Then 0.9 to 1.3 equivalents of sodium hydride and 0.9 to 1.3 equivalentsof a methylating reagent, e.g. methyl iodide, are added. The reactionmixture is stirred for 0.1-3 hours, preferably about 1 hour, at about 0to 10° C., preferably at about 5° C., and may optionally be left tostand for a further 12 hours at this temperature. The reaction mixtureis poured onto ice water and the precipitate is isolated. The residue(compound (A5)) may be purified by chromatography, preferably oversilica gel, or by crystallisation, or used as the crude product in step4A of the synthesis.

Step 4A

The amination of the compound (A5) obtained in Step 3A to yield thecompound of formula (A9) (Diagram 4A) may be carried out using themethods known from the literature of variants 4.1 A (a) M. P. V.Boarland, J. F. W. McOmie J. Chem. Soc. 1951, 1218-1221; b) F. H. S.Curd, F. C. Rose J. Chem. Soc. 1946, 343-348., 4.2 A (a) Banks J. Am.Chem. Soc. 1944, 66, 1131 b) Ghosh and Dolly J. Indian Chem. Soc. 1981,58, 512-513; c) N. P. Reddy and M. Tanaka Tetrahedron Lett. 1997, 38,4807-4810.

For example, in variant 4.1 A, 1 equivalent of the compound (A5) and 1to 3 equivalents, preferably about 2 equivalents of the compound (A6)are heated without a solvent or in an organic solvent such as forexample sulpholane, dimethylformamide, dimethylacetamide, toluene,N-methylpyrrolidone, dimethylsulphoxide or dioxane, preferablysulpholane, for 0.1 to 4 hours, preferably 1 hour, at 100 to 220° C.,preferably at about 160° C. After cooling, the product (A9) iscrystallised by the addition of organic solvents or mixtures ofsolvents, e.g. diethylether/methanol, ethyl acetate, methylene chloride,or diethylether, preferably diethylether/methanol 9/1, or purified bychromatography.

For example, in variant 4.2 A, 1 equivalent of the compound (A5) and 1to 3 equivalents of the compound (A6) are stirred with acid, for example1-10 equivalents of 10-38% hydrochloric acid and/or an alcohol, forexample ethanol, propanol, butanol, preferably ethanol, at refluxtemperature for 1 to 48 hours, preferably about 5 hours.

The product precipitated (A9) is filtered off and optionally washed withwater, dried and crystallised from a suitable organic solvent.

For example, in variant 4.3 A, 1 equivalent of the compound (A5) and 1to 3 equivalents of the compound (A7) are dissolved in a solvent, forexample toluene or dioxane and combined with a phosphine ligand, forexample 2,2″-bis-(diphenylphosphino)-1,1″-binaphthyl and a palladiumcatalyst, for example tris(dibenzylidene-acetone)-dipalladium(0) and abase, for example caesium carbonate, and refluxed for 1-24 h, preferably17 h. The reaction mixture is purified for example over silica gel andthe product (A8) is isolated from the solution or obtained by suitablecrystallisation.

The product (A8) is dissolved in a suitable solvent, for example dioxaneand mixed with acid, for example semiconcentrated hydrochloric acid, forexample in the ratio of solvent to acid of 3:1. Then the mixture isrefluxed for 1-48 h, for example 12 h, and the precipitate formed isisolated. If desired the product (A9) is purified by crystallisation.

Step 5A

Variant 5.1 A:

For example, 1 equivalent of the compound (A9) is dissolved with 1equivalent of an activating reagent, e.g.O-benzotriazolyl-N,N,N″,N″-tetramethyluronium tetrafluoroborate (TBTU)and a base, for example 1.5 equivalents of diisopropylethylamine (DIPEA)in an organic diluent, for example dichloromethane, tetrahydrofuran,dimethylformamide, N-methylpyrrolidone, dimethylacetamide, preferablydichloromethane or dimethylformamide. After the addition of 1 equivalentof the amine (A10) the reaction mixture is stirred for 0.1 to 24 hours,preferably about 2 hours at 20° C. to 100° C. The product of formula(A11) is obtained for example by crystallisation or chromatographicpurification.

The new compounds of general formula (I) may be synthesised analogouslyto the following examples of synthesis. These Examples are, however,intended only as examples of procedures to illustrate the inventionfurther, without restricting the invention to their subject matter.

The preparation of some intermediate compounds used to synthesise theexamples is also described hereinafter.

Preparation of the Acids

To synthesise the compounds of Examples 94 and 95 first an intermediate

compound Z1is prepared as described hereinafter.

50.0 g (0.48 mol) of D-alanine methyl ester x HCl and 49.1 g (0.50 mol)cyclohexanone were placed in 300 mL dichloromethane and then combinedwith 41.0 g (0.50 mol) sodium acetate and 159.0 g (0.75 mol) sodiumtriacetoxyborohydride. the mixture was stirred overnight and then 300 mLof 10% sodium hydrogen carbonate solution were added. The aqueous phasewas extracted with dichloromethane. The combined organic phases werewashed with 10% sodium hydrogen carbonate solution, dried over Na₂SO₄and evaporated down.

Yield: 72.5 g of a compound Z1a (clear liquid)

72.5 g of the compound Z1a were placed in 500 mL water and 76.6 g (0.39mol) of 2,4-dichloro-5-nitropyrimidine in 500 mL diethyl ether wereadded. At a temperature of −5° C. 100 mL 10% potassium hydrogencarbonate solution were added dropwise. The mixture was stirred for 3 hat −5° C. and for a further 12 h at ambient temperature. The organicphase was separated off and dried over Na₂SO₄. On evaporation theproduct crystallised out.

Yield: 48.0 g of a compound Z1b (yellow crystals)

48.0 g of the compound Z1b were dissolved in 350 mL glacial acetic acidand heated to 60° C. 47.5 g of iron powder were added, while thetemperature rose to 105° C. The reaction mixture was stirred for threehours at 80° C., then filtered hot through cellulose and evaporateddown. The residue was stirred in water and ethyl acetate, suctionfiltered and the light-grey precipitate was washed with ethyl acetate.The filtrate was washed with dilute ammonia and water, the organic phasewas dried over Na₂SO₄, filtered through activated charcoal andevaporated down. Some more light-grey solid was obtained.

Yield: 29.5 g of a compound Z1c (light-grey crystals)

32.1 g of the compound Z1c were placed in 300 mL dimethylacetamide andcombined with 13 mL (0.2 mol) methyl iodide. At −5° C. 6.4 g (0.16 mol)sodium hydride as a 60% dispersion in mineral oil was added batchwise.After 2 h the reaction mixture was poured onto 800 mL ice water. Theprecipitate formed was suction filtered and washed with petroleum ether.

Yield: 33.0 g of a compound Z1d (beige crystals)

4.0 g of the compound Z1d and 2.3 g (15 mmol) 4-amino-3-methylbenzoicacid were suspended in 50 mL ethanol and 120 mL water, combined with 2mL conc. hydrochloric acid and refluxed for 48 h. The precipitate formedon cooling was suction filtered and washed with water, ethanol anddiethyl ether.

Yield: 2.9 g of a compound Z1 (colourless crystals)

To synthesise the compounds Example 188 and Example 203 first of all anintermediate compound Z2

is prepared as described below.

A solution of 128.2 g (0.83 mol) D-alanine ethyl ester x HCl and 71.5 g(0.85 mol) cyclopentanone in 1500 mL dichloromethane was combined with70.1 (0.85 mol) sodium acetate and 265.6 g (1.25 mol) sodiumtriacetoxyborohydride. The reaction mixture was stirred for 12 h andthen poured into 1.5 L of a 10% sodium hydrogen carbonate solution. Theaqueous phase was extracted with dichloromethane. The combined organicphases were dried over Na₂SO₄ and evaporated down.

Yield: 143.4 g of a compound Z2a (colourless oil)

66.0 g of the compound Z2a were placed in 500 mL water and combined with85.0 g (0.44 mol) 2,4-dichloro-5-nitropyrimidine in 500 mL diethylether. At −5° C. 100 mL 10% potassium hydrogen carbonate solution wereadded dropwise and the reaction mixture was stirred for 48 h at ambienttemperature. The aqueous phase was extracted with diethyl ether, thecombined organic phases were dried over Na₂SO₄ and evaporated down. Thedark red solid was stirred with petroleum ether and suction filtered.

Yield: 88.0 g of a compound Z2b (yellow crystals)

88.0 g of the compound Z2b were dissolved in 1000 mL glacial acetic acidand at 60° C. combined batchwise with 85 g iron powder, while thetemperature rose to 110° C. It was stirred for 1 h at 60° C., thensuction filtered hot through cellulose and evaporated down. The brownsolid was stirred with 700 mL water and suction filtered.

Yield: 53.3 g of a compound Z2c (light brown crystals)

53.3 g of the compound Z2c were dissolved in 300 mL dimethylacetamideand combined with 13 mL (0.21 mol) methyl iodide. At −5° C. 5.0 g (0.21mol) sodium hydride as a 60% dispersion in mineral oil were addedbatchwise. After 12 h the reaction mixture was poured onto 1000 mL icewater and the precipitate formed was suction filtered.

Yield: 40.0 g of a compound Z2d (colourless crystals)

4.0 g of the compound Z2d and 2.8 g (16 mmol) 4-amino-3-chlorbenzoicacid were suspended in 25 mL ethanol and 60 mL water, combined with 3 mLconc. hydrochloric acid and refluxed for 43 h. The precipitate formed oncooling was suction filtered and washed with water, ethanol and diethylether.

Yield: 0.9 g of a compound Z2 (colourless crystals)

To synthesise the compounds of Examples 19, 21, 22, 23, 45, 55, 58, 116,128, 131, 133, 134, 136, 138, 177, 217, 231, 239, 46, 184, 166 and 187first of all an intermediate compound Z3

is prepared as described below.

54.0 g (0.52 mol) D-2-aminobutyric acid were suspended in 540 mLmethanol and slowly combined with 132 g (1.1 mol) thionyl chloride whilecooling with ice. The mixture was refluxed for 1.5 h and then evaporateddown. The oil remaining was combined with 540 mL tert-butylmethyletherand the colourless crystals formed were suction filtered.

Yield: 78.8 g of a compound Z3a (colourless crystals)

74.2 g of the compound Z3a and 43.5 mL (0.49 mol) cyclopentanone weredissolved in 800 mL dichloromethane. After the addition of 40.0 g (0.49mol) sodium acetate and 150.0 g (0.71 mol) sodium triacetoxyborohydrideat 0° C. the mixture was stirred for 12 h at ambient temperature andthen 500 mL of 20% sodium hydrogen carbonate solution were added. Theaqueous phase was extracted with dichloromethane. The combined organicphases were washed with water, dried over MgSO₄ and evaporated down.

Yield: 85.8 g of a compound Z3b (light yellow oil)

40.0 g of the compound Z3b and 30.0 g (0.22 mol) potassium carbonatewere suspended in 600 mL acetone and combined with 45.0 g (0.23 mol)2,4-dichloro-5-nitropyrimidin in 200 mL acetone while cooling with ice.After 12 h a further 5.0 g 2,4-dichloro-5-nitropyrimidin were added andstirred for 3 h. The reaction mixture was evaporated down, taken up in800 mL ethyl acetate and 600 mL water and the aqueous phase wasextracted with ethyl acetate. The combined organic phases were washedwith water, dried over MgSO₄ and evaporated down.

Yield: 75.0 g of a compound Z3c (brown oil)

100 g of the compound Z3c were dissolved in 650 mL glacial acetic acidand at 70° C. 20 g of iron powder were added batchwise. The mixture wasstirred for 1 h at 70° C., then for 1.5 h at 100° C. and then filteredhot through kieselgur. The reaction mixture was evaporated down, takenup in methanol/dichloromethane, applied to silica gel and purified withethyl acetate by Soxhlet extraction. The solvent was removed and theresidue stirred with methanol.

Yield: 30.0 g of a compound Z3d (light brown crystals)

25.0 g of the compound Z3d and 6.5 mL (0.1 mol) methyl iodide wereplaced in 250 mL dimethylacetamide and at −10° C. 3.8 g (0.95 mol)sodium hydride as a 60% dispersion in mineral oil was added. It wasstirred for 20 min at 0° C., then for 30 min at ambient temperature andfinally ice was added. The reaction mixture was evaporated down andcombined with 300 mL water. The precipitate formed was suction filteredand washed with petroleum ether.

Yield: 23.0 g of a compound Z3e (colourless solid)

6.0 g of the compound Z3e and 5.1 g (31 mmol) 4-amino-3-methoxybenzoicacid were suspended in 90 mL ethanol and 350 mL water, combined with 3.5mL conc. hydrochloric acid and refluxed for 48 h. The reaction mixturewas evaporated down, the residue stirred with methanol/diethyl ether andthe precipitate formed was suction filtered.

Yield: 6.3 g of a compound Z3 (light beige crystals)

To synthesise the compound of Examples 81, 82, 93, 137 first of all anintermediate compound Z4

is prepared as described below.

25.0 g (0.19 mol) of ethyl 1-aminocyclopropane-1-carboxylate x HCl and16.8 g (0.20 mol) of cyclopentanone were dissolved in 300 mL ofdichloromethane and combined with 16.4 g (0.20 mol) of sodium acetateand 61.7 g (0.29 mol) of sodium triacetoxyborohydride. It was stirredovernight and the reaction mixture was then poured onto 400 mL of 10%sodium hydrogen carbonate solution. The aqueous phase was extracted withdichloromethane. The combined organic phases were dried over Na₂SO₄ andevaporated down.

Yield: 34.5 g of a compound Z4a (colourless oil)

42.5 g (0.22 mol) of 2,4-dichloro-5-nitropyrimidine in 350 mL of diethylether were added to a mixture of 34.5 g of the compound Z4a in 350 mLwater. At −5° C. the mixture was combined with 80 mL 10% potassiumhydrogen carbonate solution and stirred overnight at ambienttemperature. The aqueous phase was extracted with diethyl ether. Thecombined organic phases were dried over Na₂SO₄ and evaporated down.

Yield: 53.8 g of a compound Z4b (brown oil)

20.1 g of the compound Z4b were dissolved in 200 mL glacial acetic acidand combined batchwise at 60° C. with 19.1 g iron powder, during whichtime the temperature rose to 100° C. The mixture was stirred for 3 h at60° C., then suction filtered through cellulose and evaporated down. Theresidue was stirred in water and ethyl acetate and the yellowprecipitate was suction filtered. The filtrate was washed with diluteammonia and water, the organic phase dried over Na₂SO₄ and evaporateddown. After the addition of diethyl ether additional productcrystallised out.

Yield: 4.0 g of a compound Z4c (yellow crystals)

7.8 g of the compound Z4c and 2.6 mL (0.04 mol) methyl iodide weredissolved in 100 mL dimethylacetamide and at −5° C. 1.5 g (0.04 mol)sodium hydride were added batchwise as a 60% dispersion in mineral oil.After 2 h the reaction mixture was poured onto ice water and theprecipitate formed was suction filtered.

Yield: 7.5 g of a compound Z4d (light brown crystals)

3.0 g of the compound Z4d and 1.9 g (11 mmol) 4-amino-3-methoxybenzoicacid were suspended in 40 mL ethanol and 80 mL water, combined with 2 mLconc. hydrochloric acid and refluxed for 20 h. A further 0.5 g of4-amino-3-methoxybenzoic acid were added and refluxed for 48 h. Theprecipitate formed on cooling was suction filtered and washed withwater, ethanol and diethyl ether.

Yield: 2.1 g of a compound Z4 (colourless crystals) m.p.: 222-223° C.

To synthesise the compounds of Examples 162, 43, 53, 161, 202, 211, 215and 212 first of all an intermediate compound Z5

is prepared as described below.

A mixture of 73.4 mL (0.5 mol) ethyl 2-bromoisobutyrate, 87.1 mL (0.75mol) of 3-methyl-1-butylamine, 82.5 g (0.6 mol) sodium iodide and 76.0 g(0.6 mol) of potassium carbonate in 1000 mL ethyl acetate was refluxedfor 3 days. Any salts present were filtered off and the filtrateevaporated down.

Yield: 97.0 g of a compound Z5a (red oil)

49.0 g (0.25 mol) of 2,4-dichloro-5-nitropyrimidine and 38.3 g (0.28mol) of potassium carbonate were suspended in 500 mL acetone and at 0°C. combined with 93.0 g of the compound Z5a in 375 mL acetone. Thereaction mixture was stirred overnight at ambient temperature, filteredand evaporated down. The residue dissolved in ethyl acetate was washedwith water and the organic phase dried over MgSO₄ and evaporated down.

Yield: 102.7 g of a compound Z5b (brown oil)

22.7 g of the compound Z5b were dissolved in 350 mL glacial acetic acidand at 60° C. combined batchwise with 17.4 g iron powder. After theaddition had ended the mixture was refluxed for 0.5 h, filtered hot andevaporated down. The residue was taken up in 200 mLdichloromethane/methanol (9:1) and washed with sodium chloride solution.The organic phase was suction filtered through kieselguhr, dried overMgSO₄, evaporated down and purified by column chromatography (eluant:ethyl acetate/cyclohexane 1:1).

Yield: 1.9 g of a compound Z5c (colourless crystals)

1.9 g of the compound Z5c were dissolved in 32 mL dimethylacetamide andwhile cooling with ice combined with 0.3 g (7 mmol) sodium hydride as a60% dispersion in mineral oil. After 10 min 0.5 mL (7 mmol) methyliodide were added and stirred for 3 h at ambient temperature. Thereaction mixture was evaporated down and combined with water. Theprecipitate formed was suction filtered and washed with petroleum ether.

Yield: 1.6 g of a compound Z5d (colourless crystals)

14.0 g of the compound Z5d and 10.0 g (0.06 mol)4-amino-3-methoxybenzoic acid were suspended in 200 mL dioxane and 80 mLwater, combined with 10 mL conc. hydrochloric acid and refluxed for 40h. The precipitate formed on cooling was suction filtered and washedwith water, dioxane and diethyl ether.

Yield: 13.9 g of a compound Z5 (colourless crystals)

To synthesise the compounds of Examples 88, 194, 229 and 89 first of allan intermediate compound Z6

is prepared as described below.

6.0 g (0.06 mol) L-2-aminobutyric acid was placed in 80 mL 0.5 Msulphuric acid and at 0° C. combined with 5.5 g (0.08 mol) sodiumnitrite in 15 mL water. The reaction mixture was stirred for 22 h at 0°C., combined with ammonium sulphate and filtered. The filtrate wasextracted with diethyl ether and the combined organic dried over MgSO₄and evaporated down.

Yield: 6.0 g of a compound Z6a (yellow oil)

200 mL methanol were combined successively with 65.0 mL (0.89 mol)thionyl chloride and 76.0 g of the compound Z6a in 50 mL methanol whilecooling with ice. The resulting mixture was stirred for 1 h at 0° C. and2 h at ambient temperature and then the methanol and remaining thionylchloride were eliminated in vacuo at 0° C.

Yield: 40.0 g of a compound Z6b (yellow oil)

30.0 mL (0.17 mol) of trifluoromethanesulphonic acid anhydride wereplaced in 150 mL dichloromethane and while cooling with ice a solutionof 20.0 g of the compound Z6b and 14.0 mL (0.17 mol) pyridine in 50 mLdichloromethane was added within one hour. The mixture was stirred for 2h at ambient temperature, any salts formed were suction filtered andthen washed with 100 mL water. The organic phase was dried over MgSO₄and evaporated down.

Yield: 42.0 g of a compound Z6c (light yellow oil)

42.0 g of the compound Z6c in 200 mL dichloromethane was added dropwisewithin one hour to a solution of 15.5 mL (0.17 mol) of aniline and 24.0mL (0.17 mol) of triethylamine in 400 mL dichloromethane while coolingwith ice. The mixture was stirred for 1 h at ambient temperature and afurther 2 h at 35° C. The reaction mixture was washed with water, driedover MgSO₄ and evaporated down. The residue remaining was purified bydistillation (95-100° C., 1*10⁻³ mbar).

Yield: 14.0 of a compound Z6d (colourless oil)

14.0 g of the compound Z6d and 16.0 g (0.1 mol) potassium carbonate weresuspended in 100 mL acetone and at 10° C. combined with 16.0 g (0.08mol) of 2,4-dichloro-5-nitropyrimidine. The mixture was stirred for 4 hat 40° C., any salts formed were suction filtered and the filtrateevaporated down. The residue was taken up in 300 mL ethyl acetate andwashed with water. The organic phase was dried over MgSO₄ and evaporateddown.

Yield: 31.0 g of a compound Z6e (brown oil)

31.0 g of the compound Z6e were dissolved in 200 mL glacial acetic acidand at 60° C. combined batchwise with 10 g iron powder, during whichtime the temperature rose to 85° C. The mixture was stirred for afurther hour at 60° C., filtered through kieselguhr and evaporated down.The residue was stirred with methanol.

Yield: 4.5 g of a compound Z6f (brown crystals)

At −20° C. 0.6 g (16 mmol) of sodium hydride as a 60% dispersion inmineral oil were added batchwise to a mixture of 4.5 g of the compoundZ6f and 1.0 mL (16 mmol) methyl iodide in 100 mL dimethylacetamide.After 1 h the reaction mixture was combined with 50 mL water andevaporated down. The residue was stirred with 200 mL water, theprecipitate is suction filtered and washed with petroleum ether.

Yield: 4.5 g of a compound Z6g (colourless crystals)

A suspension of 1.5 g of the compound Z6g and 1.4 g (8 mmol) of methyl4-amino-3-methoxybenzoate in 30 mL toluene was combined with 0.4 g (0.6mmol) of 2,2″-bis-(diphenylphosphino)-1,1″-binaphthyl, 0.23 g (0.3 mmol)of tris(dibenzylideneacetone)-dipalladium(0) and 7.0 g (21 mmol) ofcaesium carbonate and refluxed for 17 h. The reaction mixture wasapplied to silica gel and purified by column chromatography(eluant:dichloromethane/methanol 9:1).

Yield: 1.7 g of a compound Z6h (yellow crystals)

1.7 g of the compound Z6h were dissolved in 50 mL dioxane, combined with15 mL of semiconc. hydrochloric acid and refluxed for 12 h. Aftercooling the precipitate formed was suction filtered.

Yield: 1.1 g of a compound Z6 (colourless solid)

To synthesise the compound of Examples 26, 20, 32, 56, 101, 112, 209first of all an intermediate compound Z7

is prepared as described below.

50.0 g (0.36 mol) D-alanine methyl ester x HCl was suspended in 500 mLof dichloromethane and 35 mL of acetone and combined with 30.0 g (0.37mol) of sodium acetate and 80.0 g (0.38 mol) of sodiumtriacetoxyborohydride. The mixture was stirred for 12 h and then pouredonto 400 mL of 10% sodium hydrogen carbonate solution. The organic phasewas dried over Na₂SO₄ and evaporated down.

Yield: 51.0 g of a compound Z7a (yellow oil)

A suspension of 51.0 g of the compound Z7a in 450 mL water was combinedwith 80.0 g (0.41 mol) of 2,4-dichloro-5-nitropyridine in 450 mL ofdiethyl ether. At −5° C. 100 mL of 10% potassium hydrogen carbonatesolution were added dropwise. The reaction mixture was stirred for 3 h,the organic phase dried over Na₂SO₄ and evaporated down.

Yield: 74 g of a compound Z7b (yellow oil)

18.6 g of the compound Z7b were dissolved in 200 mL glacial acetic acidand at 60° C. combined batchwise with 20.0 g iron powder. The mixturewas stirred for 2 h at 60° C. and then suction filtered throughcellulose. The residue was dissolved in ethyl acetate and washed withwater and conc. ammonia. The organic phase was dried over Na₂SO₄ andevaporated down. The residue was crystallised from diethyl ether.

Yield: 9.8 g of a compound Z7c (colourless crystals)

17.0 g of the compound Z7c and 7 mL (0.1 mol) methyl iodide weredissolved in 200 mL dimethylacetamide and at −5° C. combined with 4.0 g(0.1 mol) of sodium hydride as a 60% dispersion in mineral oil. Thereaction mixture was stirred for 30 min and then poured onto 300 mL icewater. The precipitate formed was suction filtered and stirred withpetroleum ether.

Yield: 14.8 g of a compound Z7d (beige crystals)

0.9 g of the compound Z7d and 1.5 g (9 mmol) 4-amino-3-methoxybenzoicacid were heated to 210° C. for 30 min. After cooling the residue wasstirred with ethyl acetate and the precipitate obtained was suctionfiltered.

Yield: 1.2 g of a compound Z7 (grey crystals)

The following acids were prepared, for example, analogously to themethods of synthesis described:

Synthesis of the amino components L-R5

The following amines were obtained as follows:

1,1-dimethyl-2-dimethylamino-1-yl-ethylamine and1,1-dimethyl-2-piperidin-1-yl-ethylamine

The compounds were prepared according to the following references: a) S.Schuetz et al. Arzneimittel-Forschung 1971, 21, 739-763 b) V. M. Belikovet al. Tetrahedron 1970, 26, 1199-1216. c) E. B. Butler and McMillan J.Amer. Chem. Soc. 1950, 72, 2978.

Other amines were prepared as follows, in a modified manner comparedwith the literature described above.

1,1-dimethyl-2-morpholin-1-yl-ethylamine

8.7 mL morpholine and 9.3 mL 2-nitropropane were prepared, while coolingwith ice, 7.5 mL formaldehyde (37%) and 4 mL of a 0.5 mol/L NaOHsolution were slowly added dropwise (<10° C.). Then the mixture wasstirred for 1 h at 25° C. and 1 h at 50° C. The solution was treatedwith water and ether and the aqueous phase was extracted 3× with ether.The combined org. phase was dried over NaSO4 and combined with HCl indioxane (4 mol/l), the precipitate formed was suction filtered.

Yield: 21.7 of white powder

5 g of the white powder were dissolved in 80 mL methanol and with theaddition of 2 g RaNi treated with hydrogen at 35° C. and 50 psi for 40minutes. This yielded 3.6 g of 1,1-dimethyl-2-morpholin-1-yl-ethylamine.

The following amines were prepared by this method:

1,1-dimethyl-N-methylpiperazin-1-yl-ethylamine

1,1-dimethyl-2-pyrrolidin-1-yl-ethylamine

Synthesis of 1,3-dimorpholin-2-amino-propane

5 g of 1,3 Dimorpholine-2-nitropropane obtained from Messrs. Aldrich wasdissolved in 80 mL methanol and treated with hydrogen for 5.5 h at 30°C. and 50 psi with the addition of 2 g RaNi. This yielded 4.2 g of 1,3dimorpholin-2-amino-propane.

4-Aminobenzylmorpholine

The preparation of this amine is described in the following reference:

-   S. Mitsuru et al. J. Med. Chem. 2000, 43, 2049-2063

4-amino-1-tetrahydro-4H-pyran-4-yl-piperidine

20 g (100 mmol) of 4-tert-butyloxycarbony-aminopiperidine were dissolvedin 250 mL CH₂Cl₂ and stirred for 12 h at RT with 10 g (100 mmol)tetrahydro-4H-pyran-4-one and 42 g (200 mmol) NaBH(OAc)₃. Then water andpotassium carbonate were added, the org. phase was separated off, driedand the solvent was eliminated in vacuo. The residue was dissolved in200 mL CH₂Cl₂ and stirred for 12 h at RT with 100 mL trifluoroaceticacid. The solvent was eliminated in vacuo, the residue taken up withCHCl₃ and evaporated down again, then taken up in acetone and thehydrochloride was precipitated with ethereal HCl. Yield: 14.3 g (56%).

cis- and trans-4-morpholino-cyclohexylamine

Dibenzyl-4-morpholino-cyclohexylamine

3.9 g (30 mmol) of 4-dibenzylcyclohexanone were dissolved in 100 mL ofCH₂Cl₂ and stirred for 12 h at RT with 3.9 g (45 mmol) of morpholine and9.5 g (45 mmol) NaBH(OAc)₃. Then water and potassium carbonate wereadded, the org. phase was separated off, dried and the solvent waseliminated in vacuo. The residue was purified through a silica gelcolumn (about 20 mL silica gel; about 500 mL of ethyl acetate90/methanol 10+1% conc. ammonia). The appropriate fractions wereevaporated down in vacuo. Yield: 6.6 g (60%) of cis-isomer and 2 g (18%)of trans-isomer.

Alternatively the trans-dibenzyl-4-morpholino-cyclohexylamine may beprepared by the following method:

33 g (112 mmol) of 4-dibenzylcyclohexanone were dissolved in 300 mLMeOH, combined with 17.4 g (250 mmol) of hydroxylamine hydrochloride andstirred for 4 h at 60° C. The solvent was evaporated down in vacuo,combined with 500 mL water and 50 g potassium carbonate and extractedtwice with 300 mL of dichloromethane. The org. phase was dried,evaporated down in vacuo, the residue was crystallised from petroleumether, dissolved in 1.5 L of EtOH and heated to 70° C. 166 g of sodiumwere added batchwise and the mixture was refluxed until the sodiumdissolved. The solvent is eliminated in vacuo, the residue combined with100 mL water and extracted twice with 400 mL of ether. The org. phase iswashed with water, dried, evaporated down in vacuo and the trans isomeris isolated using a column (about 1.5 L silica gel; about 2 L of ethylacetate 80/methanol 20+2% conc. ammonia). Yield: 12.6 g (41.2%).

6.8 g (23 mmol) of trans-1-amino-4-dibenzylaminocyclohexane wasdissolved in 90 mL of DMF and stirred for 8 h at 100° C. with 5 mL (42mmol) of 2,2″-dichloroethyl ether and 5 g of potassium carbonate. Aftercooling 30 mL of water was added, the precipitated crystals were suctionfiltered and purified through a short column (about 20 mL silica gel,about 100 mL ethyl acetate). The residue is crystallised from methanoland conc. HCl as the dihydrochloride. Yield: 7.3 g (72.4%).

trans-4-morpholino-cyclohexylamine

7.2 g (16.4 mmol) of trans-dibenzyl-4-morpholino-cyclohexylamine weredissolved in 100 mL of MeOH and hydrogenated on 1.4 g of Pd/C (10%) at30-50° C. The solvent was eliminated in vacuo and the residue wascrystallised from ethanol and conc. HCl. Yield: 3.9 g (93%); m.p. 312°C.

The cis isomer can be prepared analogously.

cis- and trans-4-piperidino-cyclohexylamine

trans-dibenzyl-4-piperidino-cyclohexylamine

2.0 g (6.8 mmol) of trans-1-amino-4-dibenzylaminocyclohexane (seeExample 2) was dissolved in 50 mL DMF and stirred for 48 h at RT with1.6 g (7 mmol) of 1,5-dibromopentane and 2 g of potassium carbonate. Themixture was cooled, combined with water, extracted twice with 100 mL ofdichloromethane, dried and the solvent was eliminated in vacuo. Theresidue is purified over a column (about 100 mL silica gel, about 500 mLethyl acetate 80/methanol 20+1% conc. ammonia). The desired fractionswere evaporated down in vacuo and crystallised from petroleum ether.Yield: 1.2 g (49%).

trans-4-piperidino-cyclohexylamine

1.7 g (4.8 mmol) of trans-dibenzyl-4-piperidino-cyclohexylamine weredissolved in 35 mL MeOH and hydrogenated on 350 mg of Pd/C (10%) at 20°C. The solvent was eliminated in vacuo and the residue crystallised fromethanol and conc. HCl.

Yield: 1.1 g (78%).

The cis isomer may be prepared analogously.

cis- and trans-4-(4-phenyl-piperazin-1-yl)-cyclohexylamine

4.1 g (25.3 mmol) of 4-dibenzylcyclohexanone was dissolved in 50 mL ofdichloromethane and stirred for 12 h at RT with 7.4 g (25.3 mmol) ofN-phenylpyperazine and 7.4 g (35 mmol) of NaBH(OAc)₃. Then water andpotassium carbonate were added, the org. phase was separated off, driedand the solvent was eliminated in vacuo. The residue was purified over asilica gel column (ethyl acetate 80/methanol 20+0.5% conc. ammonia).Yield: 1.7 g (15.8%) of cis-isomer and 0.27 (2.5%) of trans-isomer.

trans-4-(4-phenyl-piperazin-1-yl)-cyclohexylamine

270 mg (0,61 mmol) oftrans-dibenzyl-[4-(4-phenyl-piperazin-1-yl)-cyclohexyl]-amine weredissolved in 5 mL MeOH and hydrogenated on 40 mg of Pd/C (10%) at 20-30°C. The solvent was eliminated in vacuo and the residue crystallised fromethanol and conc. HCl. Yield: 110 mg (69%).

The cis isomer may be prepared analogously.

cis- and trans-4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexylamine

9.8 g (33.4 mmol) of 4-dibenzylcyclohexanone was dissolved in 100 mLdichloromethane and stirred for 12 h at RT with 5.6 g (40 mmol) ofN-cyclopropylmethylpiperazine and 8.5 g (40 mmol) of NaBH(OAc)₃. Thenwater and potassium carbonate were added, the org. phase was separatedoff, dried and the solvent was eliminated in vacuo. The residue waspurified over a silica gel column (about 50 mL silica gel, about 3 Lethyl acetate 95/methanol 5+0.25% conc. ammonia. The appropriatefractions were evaporated down in vacuo. The faster eluting cis compoundcrystallised from ethyl acetate. The trans-compound was crystallisedfrom ethanol+conc. HCl. Yield: 8.5 g (61%) cis-isomer and 2.2 (13%)trans-isomer.

cis-4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexylamine

8.5 g (20 mmol) ofcis-dibenzyl-[4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexyl]-aminewere dissolved in 170 mL MeOH and hydrogenated on 1.7 g Pd/C (10%) at30-50° C. The solvent was eliminated in vacuo and the residue wascrystallised from ethanol and conc. HCl. Yield: 4.4 g (91%).

The trans-isomer may be prepared analogously.

SYNTHESIS OF THE EXAMPLES Example 152

0.15 g of the compound Z10, 0.14 g TBTU, 0.13 mL DIPEA were dissolved indichloromethane and stirred for 20 minutes at 25° C. Then 90 μL1-(3-aminopropyl)-4-methylpiperazine was added and stirred for a further2 hours at 25° C. The solution was then diluted with dichloromethane andextracted with water. The product was precipitated by the addition ofpetroleum ether, ether and ethyl acetate to the organic phase. Yield:0.16 g of beige solid

Example 164

0.10 g of the compound Z10, 0.1 g TBTU, 0.08 mL DIPEA were dissolved in4 mL dichloromethane and stirred for 20 minutes at 25° C. Then 44 μLdimethylaminopropylamine were added and stirred for a further 2 hours at25° C. The solution was then diluted with dichloromethane and extractedwith water. The product was precipitated by the addition of petroleumether, ether and acetone to the organic phase. Yield: 0.08 g yellowsolid.

Example 242

0.15 g of the compound Z10, 0.14 g TBTU, 0.13 mL DIPEA were dissolved in5 mL dichloromethane and stirred for 20 minutes at 25° C. Then 75 μL1-(2-aminoethyl) piperidine were added and stirred for a further 2 hoursat 25° C. The solution was then diluted with dichloromethane andextracted with water. The product was precipitated by the addition ofpetroleum ether, ether and ethyl acetate to the organic phase. Yield:0.14 g yellow solid.

Example 188

0.1 g of the compound Z2, 0.09 g TBTU, 0.05 mL DIPEA were dissolved in15 mL dichloromethane and stirred for 20 minutes at 25° C. Then 33 mg1-methyl-4-aminopiperidin were added and the mixture was stirred for afurther 3 hours at 25° C. The solution was extracted with 20 mL water,then evaporated down in vacuo. The product was crystallised using ether.Yield: 0.047 g of white crystals.

Example 203

0.1 g of the compound Z2, 0.09 g TBTU, 0.5 mL DIPEA were dissolved in 15mL dichloromethane and stirred for 30 minutes at 25° C. Then 50 mg4-amino-1-benzylpiperidin were added and the mixture was stirred for afurther 3 hours at 25° C. The solution was extracted with 20 mL water,then evaporated down in vacuo. Then the residue was chromatographed oversilica gel and the isolated product was crystallised with ether. Yield:0.015 g of white crystals.

Example 94

0.17 g of the compound Z1, 0.19 g TBTU, 0.11 mL DIPEA were dissolved in50 mL dichloromethane and stirred for 30 minutes at 25° C. Then 63 mg of1-methyl-4-aminopiperidine were added and the mixture was stirred for afurther 17 hours at 25° C. 50 mL of water and 1 g of potassium carbonatewere added to the solution and the organic phase was separated off usinga phase separation cartridge, then evaporated down in vacuo. Then theproduct was purified by silica gel chromatography and the purifiedproduct was crystallised with ether. Yield: 0.1 g of white crystals.

Example 95

0.17 g of the compound Z1, 0.19 g TBTU, 0.11 mL DIPEA were dissolved in50 mL dichloromethane and stirred for 30 minutes at 25° C. Then 77 mg ofexo-3-β-amino-tropane were added and the mixture was stirred for afurther 17 hours at 25° C. 50 mL of water and 1 g of potassium carbonatewere added to the solution and the organic phase was separated off usinga phase separation cartridge, then evaporated down in vacuo. Then theproduct was purified by silica gel chromatography and the purifiedproduct was crystallised with ether. Yield: 0.03 g of white crystals.

Example 46

0.15 g of the compound Z3, 0.12 g TBTU, 0.12 mL DIPEA were dissolved in5 mL dichloromethane and stirred for 30 minutes at 25° C. Then 50 mg1-methyl-4-aminopiperidin were added and the mixture was stirred for afurther 2.5 hours at 25° C. The solution was then extracted with waterand then evaporated down. The residue was dissolved in warm ethylacetate and crystallised from ether and petroleum ether. Yield: 0.025 gof white crystals. M.p.: 203° C. as the base

Example 80

0.2 g of the compound Z8, 0.2 g of TBTU, 0.1 mL of DIPEA were dissolvedin 10 mL dichloromethane and stirred for 30 minutes at 25° C. Then 100mg of 1-methyl-4-aminopiperidine were added and the mixture was stirredfor a further 17 hours at 25° C. The solution was then extracted with adilute potassium carbonate solution and evaporated down. The residue wascrystallised using ether. Yield: 0.12 g of white crystals

Example 190

0.2 g of compound Z8, 0.2 g of TBTU, 0.3 mL of DIPEA were dissolved in 5mL dichloromethane and stirred for 1 h at 25° C. Then 0.13 g of4-amino-1-benzylpiperidine were added and the mixture was stirred for afurther hour at 25° C. The solution was then diluted with 10 mLmethylene chloride and extracted with 20 mL water. Then the product waspurified over silica gel and crystallised from ethyl acetate and ether.Yield: 0.23 g of the compound Z8.

0.23 g of the benzylamine Z8 are dissolved in 10 mL methanol, combinedwith 50 mg of Pd/C and hydrogenated under 3 bar for 3 h at 25° C. Byadding petroleum ether and ethyl acetate white crystals are produced.These are chromatographed over silica gel and crystallised from ethylacetate and ether. Yield: 0.075 g of white crystals.

Example 196

0.1 g of compound Z10, 0.09 g of TBTU, 0.3 mL of DIPEA were dissolved in4 mL of dichloromethane and stirred for 20 minutes at 25° C. Then 67 mgxx amine was added and stirred for a further 2 hours at 25° C. Thesolution was then diluted with dichloromethane and extracted with water.It was then chromatographed over silica gel and the residue wasdissolved in acetone, combined with ethereal HCl and the precipitateformed was isolated. Yield: 0.09 g light yellow solid

Example 166

0.1 g of the compound Z10, 0.11 g of TBTU, 0.14 mL of DIPEA weredissolved in 2 mL dimethylformamide and stirred for 3 h at 50° C. Then55 mg of 4-morpholinomethylphenylamine was added. The reaction mixturewas then cooled to ambient temperature within 17 h. Then thedimethylformamide was eliminated in vacuo, the residue was taken up indichloromethane and extracted with water. It was then chromatographedover silica gel and the product crystallised from ethyl acetate andether. Yield: 0.06 g yellowish crystals

Example 81

0.2 g of the compound Z4, 0.2 g of TBTU, 0.1 mL of DIPEA were dissolvedin 10 mL dichloromethane and stirred for 30 minutes at 25° C. Then 0.1 gof 1-methyl-4-aminopiperidine were added and the mixture was stirred fora further 17 hours at 25° C. The solution was then extracted withaqueous potassium carbonate solution and then evaporated down. Theproduct was crystallised using ether. Yield: 0.16 g of white crystals.

Example 162

0.1 g of the compound Z5, 0.07 g of TBTU, 0.15 mL of DIPEA weredissolved in 5 mL dichloromethane and stirred for 20 minutes at 25° C.Then 0.04 g 1-methyl-4-aminopiperidine were added and the mixture wasstirred for a further 2 hours at 25° C. The solution was then dilutedwith 15 mL dichloromethane and extracted with 20 mL water. The residuewas dissolved in MeOH and acetone, combined with 1 mL ethereal HCl andevaporated down. A crystalline product was produced using ether, ethylacetate and a little MeOH. Yield: 0.1 g of white crystals.

Example 88

0.1 g of the compound Z6, 0.12 g of TBTU, 0.12 mL of DIPEA were in 10 mLdichloromethane dissolved and stirred for 30 minutes at 25° C. Then 0.04g of 1-methyl-4-aminopiperidine were added and the mixture was stirredfor a further 2 hours at 25° C. The solution was then diluted with 10 mLdichloromethane and extracted with 10 mL water. A crystalline productwas produced using ether, ethyl acetate and petroleum ether. Yield: 0.6g of white crystals.

Example 89

0.1 g of the compound Z6, 0.08 g of TBTU, 0.08 mL of DIPEA weredissolved in 10 mL dichloromethane and stirred for 30 minutes at 25° C.Then 37 μL g N,N-dimethylneopentanediamine were added and the mixturewas stirred for a further 2 hours at 25° C. The solution was thendiluted with 10 mL dichloromethane and extracted with 10 mL water. Theproduct was then chromatographed over silica gel and crystallised fromethyl acetate, ether and petroleum ether. Yield: 0.005 g of whitecrystals.

Example 26

0.15 g of the compound Z7, 0.16 g of TBTU, 1 mL of DIPEA were dissolvedin 5 mL dichloromethane and stirred for 30 minutes at 25° C. Then 0.1 g4-morpholinocyclohexylamine were added and the mixture was stirred for afurther 17 hours at 25° C. The residue was then combined with 10 mL of10% potassium carbonate solution, the precipitate was isolated andwashed with water. It was then dissolved in dichloromethane andevaporated down again. The product was crystallised from ethyl acetate.Yield: 0.1 g of white crystals.

Example 9

150 mg of the compound Z9 and 93 mg of amine were dissolved in 5 mLdichloromethane and stirred with 160 mg of TBTU and 1 mL of DIPEA for 12h at RT. The solvent was eliminated in vacuo, the residue was combinedwith 10 mL of 10% potassium carbonate solution. The precipitate wassuction filtered, washed with water, taken up in dichloromethane, driedand the solvent eliminated in vacuo. The residue was crystallised fromethyl acetate. Yield: 82.0 mg; m.p. 253° C. (as base).

Example 16

150 mg of the compound Z8 and 73 mg oftrans-4-piperidino-cyclohexylamine were dissolved in 5 mLdichloromethane and stirred with 160 mg (0.50 mmol) of TBTU and 1 mL ofDIPEA for 12 h at RT. The solvent was eliminated in vacuo, the residuewas combined with 10 mL of 10% potassium carbonate solution. Theprecipitate was suction filtered, washed with water, taken up indichloromethane, dried and the solvent eliminated in vacuo. The residuewas crystallised from ethyl acetate. Yield: 87.0 mg; m.p. 237° C. (asbase).

Example 37

100 mg of the compound Z9 and 42 mg of 3-amino-1-ethyl-pyrrolidine weredissolved in 10 mL dichloromethane and stirred with 90 mg of TBTU and0.5 mL of DIPEA for 12 h at RT. The solvent was eliminated in vacuo, theresidue was combined with 10 mL of 10% potassium carbonate solution. Theprecipitate was suction filtered, washed with water, taken up indichloromethane, dried and the solvent was eliminated in vacuo. Theresidue was crystallised from ethyl acetate/petroleum ether. Yield: 24.0mg.

Example 120

100 mg of the compound Z11 and 73 mg of 4-amino-1tetrahydro-4H-pyran-4-yl-piperidine were dissolved in 10 mLdichloromethane and stirred with 90 mg of TBTU and 0.5 mL of DIPEA for 1h at RT. The solvent was eliminated in vacuo, the residue was combinedwith 10 mL of 10% potassium carbonate solution. The precipitate wassuction filtered, washed with water, taken up in dichloromethane, driedand the solvent was eliminated in vacuo. The residue was crystallisedfrom ethyl acetate/petroleum ether. Yield: 89 mg.

Example 212

150 mg of the compound Z5 and 150 mg oftrans-4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexylamine (as thehydrochloride) were dissolved in 5 mL of dichloromethane and stirredwith 160 mg of TBTU and 2 mL of DIPEA for 2 h at RT. The solvent waseliminated in vacuo, the residue was combined with 10 mL of 10%potassium carbonate solution. The precipitate was suction filtered,washed with water, taken up in dichloromethane, dried and the solventeliminated in vacuo. The residue was purified over a column (20 mLsilica gel, 300 mL ethyl acetate 90/methanol 10+2% conc. ammonia). Theappropriate fractions were evaporated down in vacuo and crystallisedfrom ethyl acetate. Yield: 140 mg; m.p. 187° C. (as base).

Example 232

390 mg of the compound Z11 and 240 mg oftrans-4-(4-tbutyloxycarbonyl-piperazin-1-yl)-cyclohexylamine weredissolved in 2.5 mL of NMP and stirred with 482 mg of TBTU and 1 mLtriethylamine for 2 h at RT. Then 100 mL of water and 200 mg ofpotassium carbonate were added, the precipitate was suction filtered,washed with water and purified through a silica gel column. Theappropriate fractions were evaporated down in vacuo, dissolved in 2 mLdichloromethane, combined with 2 mL of trifluoroacetic acid and stirredfor 2 h at RT, combined with another 100 ml of water and 200 mgpotassium carbonate and the precipitate was suction filtered and washedwith water. Then the precipitate was purified through a silica gelcolumn. The appropriate fractions were evaporated down in vacuo and theresidue was crystallised from ethanol and conc. hydrochloric acid.Yield: 95 mg; m.p. 291° C.

Example 213

60 mg of the compound of Example 232 was dissolved in 10 mL ethylacetate and stirred with 1 mL of acetic anhydride and 1 mL oftriethylamine for 30 min. at RT. The solvent was eliminated in vacuo,the residue combined with water and ammonia, the crystals precipitatedwere suction filtered and washed with water and a little cold acetone.Yield: 40 mg; m.p. 248° C.

Example 218

1.2 g of the compound Z9 and 0.5 g of 1,4-dioxaspiro[4.5]dec-8-ylaminewere dissolved in 20 mL dichloromethane and stirred with 1.28 g of TBTUand 4 mL of triethylamine for 12 h at RT. Then 50 mL of water and 0.5 gof potassium carbonate were added, the org. phase was separated off,dried and evaporated down in vacuo. The residue was crystallised fromethyl acetate, combined with 25 mL of 1 N hydrochloric acid and 20 mL ofmethanol and stirred for 30 min at 50° C.

The methanol was eliminated in vacuo, the precipitate was suctionfiltered, washed with water and dried.

The residue was taken up in 20 mL dichloromethane, stirred with 0.5 g ofthiomorpholine and 0.5 g of NaBH(OAc)₃ for 12 h at RT. Then water andpotassium carbonate were added, the org. phase was separated off, driedand the solvent was eliminated in vacuo. The residue was purified over asilica gel column. The appropriate fractions were evaporated down invacuo and the hydrochloride was precipitated with ethereal HCl. Yield:86 mg of trans-isomer; amorphous powder.

Example 187

200 mg of the compound Z3 in 5 mL dichloromethane was combined with 0.1mL of diisopropylethylamine and 180 mg of TBTU and stirred for 30 min.Then 191 mg of 4-(4-methyl-piperazin-1-yl)-phenylamine were added andthe mixture was stirred overnight. The reaction mixture was combinedwith water and the aqueous phase extracted with dichloromethane. Thecombined organic phases were dried over Na₂SO₄ and Z9 brated down. Theresidue was purified by column chromatography (eluant:dichloromethane/methanol 100:7).

Yield: 128 mg (light yellow crystals)

The compounds of formula (I) listed in Table 1, inter alia, are obtainedanalogously to the procedure described hereinbefore. The abbreviationsX₁, X₂, X₃, X₄ and X₅ used in Table 1 in each case denote a link to aposition in the general formula shown under Table 1 instead of thecorresponding groups R¹, R², R³, R⁴ and L-R⁵.

TABLE 1

Ex- Config. am- H460- R¹ or ple HELA VINC R¹ R² R² R³ R⁴ L_(n)-R⁵ _(m)m.p  1 0.046 0.604 H

R

 2 0.056 0.971 H

R

 3 0.061 H

R

H

 4 0.098 H

R

H

 5 0.052 0.863 H

R

 6 0.053 0.822 H

R

 7 0.084 0.865 H

R

 8 0.063 H

R

H

 9 0.057 0.207 H

R

253  10 0.091 H

R

H

 11 0.086 1.300 H

R

H

 12 0.099 1.069 H

R

H

 13 0.026 1.320 H

R

 14 0.055 3.000 H

R

H

 15 0.020 1.000 H

R

231  16 0.017 0.483 H

R

237  17 0.024 0.730 H

R

 18 0.040 1.764 H

R

H

 19 0.013 0.747 H

R

254  20 0.083 3.000 H

R

 21 0.009 0.488 H

R

 22 0.008 0.347 H

R

 23 0.013 0.679 H

R

 24 0.017 0.277 H

R

152  25 0.038 1.000 H

R

254  26 0.059 0.424 H

R

 27 0.014 0.164 H

R

292  28 0.018 0.160 H

R

160  29 0.049 1.000 H

R

251  30 0.012 0.574 H

R

 31 0.023 3.000 H

R

H

 32 0.049 3.000 H

R

 33 0.097 3.000 H

R

H

 34 0.055 1.000 H

R

242  35 0.088 1.000 H

R

213  36 0.021 1.000 H

R

232  37 0.072 0.762 H

R

160  38 0.087 0.278 H

R

225  39 0.075 1.000 H

R

H

 40 0.038 0.187 H

R

226  41 0.083 3.000 H

R

 42 0.076 2.310 H

R

 43 0.094 3.000 X₁—CH₃

218  44 0.009 0.204 H

R

H

 45 0.022 0.792 H

R

 46 0.012 0.208 H

R

203  47 0.028 H

R

H

 48 0.083 3.000 H

R

H

 49 0.059 0.529 H

R

 50 0.081 0.436 H

R

 51 0.080 0.150 H

R

 52 0.079 0.153 H

R

 53 0.076 0.245

 54 0.031 0.226 H

R

 55 0.013 0.086 H

R

 56 0.064 0.324 H

R

 57 0.038 0.067 H

R

 58 0.010 0.023 H

R

 59 0.095 1.000 H

R

 60 0.041 0.189 H

R

 61 0.065 1.040

217  62 0.058 0.538 H

R

259  63 0.081 0.206 H

R

184  64 0.064 0.894 H

R

175  65 0.052 0.216 H

R

172  66 0.064 0.250 H

R

164  67 0.052 0.566 H

R

115  68 0.092 1.242 H

R

H

 69 0.055 0.633 H

R

H

 70 0.092 1.000 H

R

H

 71 0.035 0.227 H

R

146  72 0.050 H

R

 73 0.091 H

R

H

 74 0.043 H

R

 75 0.046 0.557 H

R

 76 0.068 H

R

 77 0.055 1.000 H

R

H

 78 0.035 0.610 H

R

H

 79 0.043 H

R

H

 80 0.038 0.286 H

R

 81 0.050 0.237 H

R

194  82 0.083 1.580 H

R

 83 0.069 0.263 H

R

 84 0.015 0.312 H

R

 85 0.025 0.754 H

R

H

 86 0.038 0.024 H

R

 87 0.029 0.066 H

R

 88 0.020 1.018 H

R

 89 0.047 0.245 H

R

 90 0.032 0.137 H

R

 91 0.041 1.780 H

R

 92 0.043 H

R

H

181  93 0.060 H

R

H

 94 0.018 0.510 H

R

178  95 0.047 1.000 H

R

 96 0.011 0.577 H

R

203  97 0.032 0.066 H

R

179  98 0.077 1.319 H

R

 99 0.025 0.209 H

R

280 100 0.058 0.124 H

R

233 101 0.031 0.124 H

R

102 0.006 0.053 H

R

103 0.005 0.076 H

R

104 0.041 0.133 H

R

105 0.015 0.055 H

R

229 106 0.025 1.000 H

R

213 107 0.043 0.363 H

R

285 108 0.016 1.000 H

R

109 0.031 0.760 H

R

110 0.027 0.122 H

R

278 111 0.023 0.503 H

R

112 0.075 0.345 H

R

264 113 0.037 0.687 H

R

279 114 0.064 0.766 H

R

234 115 0.016 0.076 H

R

116 0.006 0.174 H

R

117 0.010 0.370 H

R

118 0.010 0.279 H

R

119 0.008 0.438 H

R

120 0.014 0.374 H

R

121 0.011 0.427 H

R

122 0.009 0.261 H

R

123 0.043 0.490 H

R

124 0.006 0.391 H

R

125 0.049 0.795 H

R

283 126 0.051 0.742 H

R

238 127 0.045 0.787 H

R

221 128 0.015 0.282 H

R

257 129 0.035 0.646 H

R

284 130 0.015 0.091 H

R

236 131 0.023 0.101 H

R

141 132 0.062 1.000 H

R

268 133 0.011 0.075 H

R

272 134 0.015 0.063 H

R

319 135 0.012 0.699 H

R

289 136 0.041 0.821 H

R

201 137 0.039 0.148 H

R

223 138 0.043 1.137 H

R

217 139 0.097 3.000 H

R

112 140 0.029 1.970 H

R

215 141 0.057 H

R

198 142 0.030 H

R

192 143 0.086 H

R

H

139 144 0.044 H

R

H

191 145 0.043 3.000 H

R

146 0.066 0.966 H

R

147 0.055 1.760 H

R

H

148 0.087 H

R

149 0.085 H

R

150 0.043 H

R

H

151 0.043 H

R

155 152 0.081 H

R

147 153 0.072 2.640 H

R

128 154 0.097 H

R

H

155 0.079 H

R

H

156 0.048 0.481 H

R

173 157 0.051 H

R

134 158 0.043 0.536 H

R

230 159 0.029 1.000 H

R

260 160 0.037 0.728 H

R

193 161 0.081 X₁—CH₃

199 162 0.071 0.903 X₁—CH₃

254 163 0.071 1.000 H

R

249 164 0.030 0.975 H

R

165 0.046 0.668 H

R

166 H

R

167 0.034 0.817 H

R

168 0.042 0.088 H

R

169 0.044 0.503 H

R

170 0.045 0.427 H

R

170 171 0.031 0.790 H

R

196 172 0.020 0.772 H

R

166 173 0.070 0.871 H

R

174 0.000 0.155 H

R

175 0.000 0.296 H

R

176 0.000 0.301 H

R

177 0.000 0.082 H

R

178 0.000 1.000 H

R

179 0.000 1.000 H

R

180 0.000 0.147 H

R

136 181 0.000 0.754 H

R

182 H

R

183 H

R

184 H

R

185 H

R

217 186 H

R

287 187 H

R

223 188 H

R

161 189 H

R

267 190 H

R

191 H

R

192 H

R

193 H

R

194 H

R

195 H

R

196 H

R

197 H

198 H

R

301 199 H

R

291 200 H

R

201 H

R

202

203 H

R

204 H

R

205 H

R

255 206 H

R

190 207 H

R

236 208 H

R

192 209 H

R

211 210 H

R

210 211 X₁—CH₃

182 212 X₁—CH₃

187 213 H

R

248 214 H

R

338 215 X₁—CH₃

232 216 H

R

217 217 H

R

139 218 H

R

219 H

R

298 220 H

R

279 221 H

R

336 222 H

R

241 223 1 H

R

224 1.056 1 H

R

225 1.18 1 H

R

H

226 0.295 1 H

R

227 0.853 0.946 H

R

228 1 H

R

229 0.381 H

R

230 0.193 H

R

231 0.17 H

R

232 1 H

R

233 H

R

234 H

R

235 H

R

236 H

R

237 0.012 1 H

R

238 0.015 1 H

R

239 0.051 0.07 H

R

240 0.017 0.054 H

R

241 0.044 0.093 H

R

242 0.019 0.524 H

R

243 0.018 0.975 H

R

244 0.0115 H

R

As has been found, the compounds of general formula (I) arecharacterised by their wide range of applications in the therapeuticfield. Particular mention should be made of those applications in whichthe inhibition of specific cell cycle kinases, particularly theinhibiting effect on the proliferation of cultivated human tumour cellsbut also the proliferation of other cells, such as endothelial cells,for example, plays a part.

As could be demonstrated by FACS analysis, the inhibition ofproliferation brought about by the compounds according to the inventionis mediated by the arrest of the cells, particularly at the G2/M phaseof the cell cycle. The cells arrest, independently of the cells used,for a specific length of time in this phase of the cell cycle beforeprogrammed cell death is initiated. An arrest in the G2/M phase of thecell cycle is triggered, for example, by the inhibition of specific cellcycle kinases. Studies in model organisms such as Schizosaccharomycespombe or Xenopus, or investigations in human cells have shown that thetransition from the G2 phase to mitosis is regulated by the CDK1/cyclinB kinase (Nurse, 1990). This kinase, which is also known as the “mitosispromoting factor” (MPF), phosphorylates and thereby regulates a numberof proteins, such as e.g. nuclear lamins, kinesin-like motor proteins,condensins and Golgi matrix proteins, which play an important part inthe breakdown of the nuclear envelope, in centrosome separation, theformation of the mitotic spindle apparatus, chromosome condensation andthe breakdown of the Golgi apparatus (Nigg. E., 2001). A murine cellline with a temperature-sensitive CDK1 kinase mutant shows a rapidbreakdown of the CDK1 kinase and a subsequent arrest in the G2/M phaseafter a temperature increase (Th'ng et al., 1990). The treatment ofhuman tumour cells with inhibitors against CDK1/cyclin B such as e.g.butyrolactone also leads to an arrest in the G2/M phase and subsequentapoptosis (Nishio, et al. 1996). Another kinase which is involved in theG2 and mitosis phase is polo-like kinase 1 (Plk1), which is responsiblefor the maturation of the centrosomes, for the activation of thephosphatase Cdc25C, as well as for the activation of the anaphasepromoting complex (Glover et al., 1998, Qian, et al., 2001). Theinjection of Plk1 antibodies leads to a G2 arrest in untransformed cellswhereas tumour cells arrest in the mitosis phase (Lane and Nigg, 1996).In addition, the protein kinase aurora B has been described as having anessential function during entry into mitosis. Aurora B phosphorylateshistone H3 at Ser11 and thereby initiates chromosome condensation (Hsu,J. Y. et al., 2000). A specific cell cycle arrest in the G2/M phase may,however, also be triggered e.g. by the inhibition of specificphosphatases such as e.g. Cdc25C (Russell and Nurse, 1986). Yeasts witha defective cdc25 gene arrest in the G2 phase, while overexpression ofcdc25 leads to early entry into the mitosis phase (Russell and Nurse,1987). However, an arrest in the G2/M phase can also be triggered by theinhibition of certain motor proteins, so-capped kinesins such as e.g.Eg5 (Mayer et al., 1999), or by agents which stabilise or destabilisemicrotubules (e.g. colchicin, taxol, etoposide, vinblastin, vincristin)(Schiff and Horwitz, 1980).

In view of their biological properties the compounds of general formulaI according to the invention, their isomers and their physiologicallyacceptable salts are suitable for the treatment of diseasescharacterised by excessive or abnormal cell proliferation.

Such diseases include, for example: viral infections (e.g. HIV andKaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis,arthritis, Alzheimer's disease, glomerulonephritis and wound healing);bacterial, fungal and/or parasitic infections; leukaemias, lymphoma andsolid tumours; skin diseases (e.g. psoriasis); bone diseases;cardiovascular diseases (e.g. restenosis and hypertrophy). They are alsosuitable for protecting proliferating cells (e.g. hair, intestinal,blood and progenitor cells) from damage to their DNA caused byradiation, UV treatment and/or cytostatic treatment (Davis et al.,2001).

The new compounds may be used for the prevention, short-term orlong-term treatment of the abovementioned diseases, also in combinationwith other active substances used for the same indications, e.g.cytostatics.

The activity of the compounds according to the invention was determinedin the cytotoxicity test on cultivated human tumour cells and/or in aFACS analysis, for example on HeLaS3 cells. In both test methods, thecompounds exhibited a good to very good activity, i.e. for example anEC₅₀ value in the HeLaS3 cytotoxicity test of less than 5 μmol,generally less than 1 μmol.

Measurement of Cytotoxicity on Cultivated Human Tumour Cells

To measure the cytotoxicity on cultivated human tumour cells, cells ofthe cervical cancer tumour cell line HeLaS3 (obtained from American TypeCulture Collection (ATCC)) in Ham's F12 Medium (Life Technologies) and10% foetal calf serum (Life Technologies) were cultivated and harvestedin the logarithmic growth phase. Then the HeLaS3 cells were placed in96-well plates (Costar) at a density of 1000 cells per well andincubated overnight in an incubator (at 37° C. and 5% CO₂), while oneach plate 6 wells were filled only with medium (3 wells as a control ofthe medium, 3 wells for incubation with reduced AlamarBlue). The activesubstances were added to the cells in various concentrations (dissolvedin DMSO; final concentration: 1%) (in each case as a triplemeasurement). After 72 hours' incubation, 20 μl of AlamarBlue (AccuMedInternational) were added to each well, and the cells were incubated fora further 7 hours. As a control, 20 μl of reduced Alamar Blue(AlamarBlue reagent which had been autoclaved for 30 min) were added to3 wells. After 7 h incubation the colour change of the AlamarBluereagent in the individual wells was determined in a Perkin Elmerfluorescence spectrophotometer (excitation 530 nm, emission 590 nm,slits 15, integrate time 0.1). The amount of AlamarBlue reagent reactedrepresents the metabolic activity of the cells. The relative cellactivity was calculated as a percentage of the control (HeLa S3 cellswithout inhibitor) and the active substance concentration which inhibitsthe cell activity by 50% (IC⁵⁰) was obtained. The values were calculatedfrom the average of three individual measurements, correcting for thecontrol value (medium control).

FACS Analysis

Propidium iodide (PI) binds stoichiometrically to double-stranded DNA,and is thus suitable for determining the percentage of cells in the G1,S and G2/M phase of the cell cycle on the basis of the cell DNA content.Cells in the G0 and G1 phase have a diploid DNA content (2N), whereascells in G2 or mitosis have a 4N DNA content.

For PI staining, 0.4 million HeLaS3 cells were seeded, for example, on a75 cm² cell culture flask, and after 24 h either 1% DMSO was added ascontrol or the substance was added in various concentrations (in 1%DMSO). The cells were incubated for 24 h with the substance or withDMSO, before the cells were washed with 2×PBS and detached withtrypsin/EDTA. The cells were centrifuged (1000 rpm, 5 min, 4° C.), andthe cell pellet was washed 2× with PBS, before the cells wereresuspended in 0.1 ml of PBS. Then the cells were fixed with 80% ethanolfor 16 hours at 4° C. or alternatively for 2 hours at −20° C. The fixedcells (10⁶ cells) were centrifuged (1000 rpm, 5 min, 4° C.), washed withPBS and then centrifuged again. The cell pellet was resuspended in 2 mlof Triton X-100 in 0.25% PBS, and incubated for 5 min on ice, before 5ml of PBS were added and the mixture was centrifuged again. The cellpellet was resuspended in 350 μl of PI stain solution (0.1 mg/ml of RazeA, 10 μg/ml of presidium iodide in 1×PBS). The cells were incubated for20 min in the dark with the stain buffer before being transferred intosample measuring vessels for the FACS scan. The DNA measurement wascarried out in a Becton Dickinson FACS Analyzer, with an argon laser(500 mW, emission 488 nm), and the DNA Cell Quest Program (BD). Thelogarithmic PI fluorescence was determined with a band-pass filter (BP585/42). The cell populations in the individual phases of the cell cyclewere quantified with the ModFit LT program of Becton Dickinson.

The compounds of general formula (I) may be used on their own orcombined with other active substances according to the invention,optionally also in conjunction with other pharmacologically activesubstances. Suitable preparations include for example tablets, capsules,suppositories, solutions, particularly solutions for injection (s.c.,i.v., i.m.) and infusion, syrups, emulsions or dispersible powders. Theamount of pharmaceutically active compound in each case should be in therange from 0.1-90 wt. %, preferably 0.5-50 wt. % of the totalcomposition, i.e. in amounts which are sufficient to achieve the dosagerange given below. The doses specified may, if necessary, be givenseveral times a day.

Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharin, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g.with the addition of preservatives such as p-hydroxybenzoates, orstabilisers such as alkali metal salts of ethylenediamine tetraaceticacid, optionally using emulsifiers and/or dispersants, while if water isused as the diluent organic solvents may optionally be used assolubilisers or auxiliary solvents, and transferred into injection vialsor ampoules or infusion bottles.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Suitable excipients may be, for example, water, pharmaceuticallyacceptable organic solvents, such as paraffins (e.g. petroleumfractions), oils of vegetable origin (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolin, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silica and silicates),sugar (e.g. glucose, lactose and dextrose), emulsifiers (e.g. lignin,spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

The preparations are administered in the usual way, preferably by oralor transdermal route, particularly preferably by oral route. Whenadministered orally the tablets may, of course, contain additives, suchas e.g. sodium citrate, calcium carbonate and dicalcium phosphatetogether with various additives, such as starch, preferably potatostarch, gelatine and the like, in addition to the abovementionedcarriers. Lubricants such as magnesium stearate, sodium laurylsulphateand talc may also be used to form tablets. In the case of aqueoussuspensions the active substances may be combined with various flavourenhancers or colourings in addition to the abovementioned excipients.

For parenteral use, solutions of the active substances may be preparedusing suitable liquid carrier materials.

The dosage for intravenous use is 1-1000 mg per hour, preferably between5-500 mg per hour.

However, it may optionally be necessary to deviate from the amountsspecified, depending on the body weight or method of administration, theindividual response to the medication, the nature of the formulationused and the time or interval over which it is administered. Thus, insome cases, it may be sufficient to use less than the minimum quantityspecified above, while in other cases the upper limit specified willhave to be exceeded. When large amounts are administered it may beadvisable to spread them over the day in a number of single doses.

The formulation examples that follow illustrate the present inventionwithout restricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance 100 mg lactose 140 mg corn starch240 mg polyvinylpyrrolidone  15 mg magnesium stearate  5 mg 500 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tablets per tablet active substance 80 mg lactose 55 mg corn starch190 mg  microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mgsodium-carboxymethyl starch 23 mg magnesium stearate  2 mg 400 mg 

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. Thesodiumcarboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize.

C) Ampoule solution active substance 50 mg sodium chloride 50 mg waterfor inj.  5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

1. A compound of formula (I) as shown in the following Table

Config. R¹ or Example R¹ R² R² R³ R⁴ L_(n)-R⁵ _(m) 46 H

R

or a pharmacologically acceptable acid addition salt thereof, whereinthe abbreviations X₂, X₃, X₄ and X₅ used in the Table in each casedenote a link to a position in the general formula shown under the Tableinstead of the corresponding groups R², R³, R⁴ and L-R⁵.